The mussel byssal thread tethers mussels to rocks in the ocean and is subjected to cyclic stresses similar to those experienced in the vascular system. The heart continuously pumps blood, stressing vessel walls and valves; ocean waves continuously hit the shore, stressing the threads attaching mussels to rocks. Interestingly, these threads, when strained beyond their yield point, show a time-dependent ability to recover their mechanical properties. This self-healing property has been attributed to the high histidine content at the ends of mussel thread collagen. It is believed that multiple histidines coordinate around single metal ions at the ends of the collagen fibrils. These coordination bonds require less force to break than covalent bonds, serving as the weakest links of the thread. In a time-dependent manner these bonds are believed to reform, resulting in the partial recovery of the Young's modulus of the byssal thread. Using the molecular architecture of the byssal thread as inspiration, we propose to develop self-healing materials by incorporating metal-binding peptide sequences into the material's polymer backbone. Specifically, we plan to develop polyethylene glycol-based hydrogels, which have been investigated for many medical applications, including tissue adhesives, cellular scaffolds, and drug-delivery systems. Concurrently, we plan to develop an understanding of the molecular basis of the mussel byssal threads and the material's self- healing properties, using single-molecule force spectroscopy. We believe single-molecule experiments will provide insight into the bulk material mechanical properties and provide guidance for future material design. Robust materials are needed to stand up to the harsh environment of the vascular system; no synthetic materials have been shown to be ideal for small vessel grafts. Self-healing biomaterials would be ideal for vascular tissue replacements, providing mechanical stability unlike current synthetic polymers. Currently, no synthetic materials exist that are ideal for small vessel grafts such as those used in coronary artery bypass. PUBLIC HEALTH RELEVANCE: For those patients who do not have suitable grafts (usually from veins in the leg), only inferior quality substitutes exist. We propose to develop materials that have the ability to self-heal, which are inspired by the mussel byssal thread, and may prove to be good tissue replacements for small vessels.